The endothelins (ET) are a new family of vasoactive peptides produced and released by vascular endothelial cells upon various physical and chemical stimuli. We investigated: 1) The pharmacological effects of exogenously administered ET on blood pressure, heart rate, cardiac output, regional blood flow and peripheral resistance in rats under several experimental conditions. 2) the presence of immunoreactive ET in plasma and in other body fluids, by radioimmunoassay and high performance liquid chromatography. 3) The possible involvement of ET in the pathogenesis of hypertension in man. ET had a unique biphasic cardiovascular effect with an initial decrease in blood pressure followed by a prolonged hypertensive response. The pressor phase could be blocked by verapamil but not by other agents. The depressor phase could not be blocked by anything tested. Cardiac output initially increased and later markedly decreased. There was a selective effect on individual vascular beds with a maximal increase in resistance in the renal bed. The renal vascular effect, but not the systemic effect, was enhanced in rats on a high salt diet. ET induced an increase in circulating atrial natriuretic factor. The cardiovascular effects were markedly diminished in rats with experimental CHF. Whereas ET was antidiuretic and antinatriuretic, its' precursor, Big-ET, had a substantial natriuretic effect. The levels of ET in the plasma were very low both in man and in rats. Other body fluids such as urine, cerebrospinal fluid, saliva and synovial fluid contained much higher concentrations of the peptide. In hypertensive patients plasma levels of ET were normal but urinary levels were markedly decreased, especially in a subgroup of salt sensitive hypertensives. We conclude that : 1) ET is a potent vasoactive peptide. 2) This activity is mediated by calcium channels and not by other hormonal systems. 3) ET may be involved in nonvascular physiologic events. 4) Renal ET may have a role in the pathogenesis of hypertension.